Thiotepa is an ethylenimine type compound, also referred to as 1,1',1"-phosphinothioylidynetrisaziridine which has the following structure: ##STR1## It is a polyfunctional alkylating agent used in the chemotherapy of various neoplastic diseases including adenocarcinoma of the breast and ovaries and for the treatment of superficial papillary carcinoma of the urinary bladder. Preparation of the compound is reported in U.S. Pat. Nos. 2,670,347 and 4,918,199.
At present, thiotepa is commercially provided in a pharmaceutical dosage form for parenteral use as a sterile powder for reconstitution containing a mixture of thiotepa powder, sodium chloride and sodium bicarbonate. When reconstituted with Sterile Water for Injection, the resulting solution has a pH of about 7.6. Whether in its original powder form or reconstituted, it must be stored under refrigerated conditions (2.degree.-8.degree. C.). The reconstituted solution is only stable for about 5 days as a reconstituted solution, even under refrigerated conditions.
The thiotepa sterile powder is known to degrade rapidly to a hazy solution upon reconstitution with aqueous media. It is theorized that the haze is due to a polymerization reaction which occurs when the compound is exposed to water. It is known that as thiotepa bulk degrades, water is consumed, and a decrease of water content can be detected. It has also been reported that the solution is more stable at an alkaline pH.
Several attempts have been made to stabilize the thiotepa composition and slow down or prevent the haze formation that occurs in aqueous media. Sodium bicarbonate was added to the powder formulation as a stabilizer based on the theory that the presence of the bicarbonate would render the environment of the powder alkaline and stabilize the thiotepa via a pH mechanism. However, contrary to this theory, the data indicated that the presence of sodium bicarbonate in the sterile powder did not stabilize thiotepa and prevent the rapid haze formation.
Thus, there is a need for a formulation of thiotepa which has improved stability and which does not undergo such rapid haze formation upon reconstitution with aqueous media.
It is known in the art that freeze-drying (lyophilization) of a product which is relatively unstable in aqueous solution can result in a product that is stabilized and therefore has a longer shelf life than an aqueous solution Additionally, a freeze-dried product has an advantage over a product in powder form in that it is rapidly soluble and easily reconstituted prior to administration by injection. Another advantage of freeze-drying a product unstable in aqueous solution is that it can be processed and filled into dosage containers in a liquid state, dried at low temperatures thereby eliminating adverse thermal effects, and stored in the dry state where it may be more stable. (See Remington's Pharmaceutical Sciences, 15th edition, pp. 1483-1485 (1975)). Thus, freeze-drying would be an ideal method of obtaining a formulation of thiotepa which would exhibit the improved stability.
However, the present inventors have found that lyophilization of an aqueous solution of thiotepa did not result in an appreciable improvement in stability or an appreciable decrease in haze formation upon reconstitution.